The present invention relates to fused pyridazine derivatives, methods for the preparation of such fused pyridazines, and use of such fused pyridazines in the treatment of certain diseases or conditions. In particular, the present invention relates to fused pyridazine derivatives useful as cyclin dependent kinase inhibitors and use of the fused pyridazines in the treatment of disorders mediated by inappropriate cyclin dependent kinase activity.
Effective chemotherapy, as well as radiotherapy, for cancer treatment, which has acceptable toxicity to normal cells, is a continuing goal in the oncology field. Numerous cytotoxic agents are used in the treatment of cancer, including cytotoxic agents that adversely affect rapidly dividing cells, including normal cells, that are in the process of cell division. Typically, such agents may have effect on the cell cycle at G1—the period between mitosis and DNA synthesis; S—the period of DNA synthesis; G2—the pre-mitotic interval; and/or M—the period of mitosis and are termed phase specific agents. Such agents are not effective in Go, the quiescent or resting cell phase. Therefore, such anti-neoplastic agents are active against cells in the process of cell division and are most effective against cancers that have a large growth fraction, that is, tumors that have a high percentage of dividing cells. Problematically, however, such agents also have an adverse effect on rapidly proliferating, normal tissues such as hair follicles and intestinal epithelium (See Goodman Et Gilman's, The Pharmacologic Basis Of Therapeutics 9th Ed., pages 1230-1232.) which may lead to chemotherapy-induced alopecia (CIA) or mucositis. CIA as well as mucositis are frequent emotionally and/or physically distressing side effects of cancer chemo- and radiotherapies.
Protein kinases catalyze the phosphorylation of various residues in proteins including proteins involved in the regulation of cell growth and differentiation. Protein kinases play a critical role in the control of cell growth and differentiation and are key mediators of cellular signals leading to the production of growth factors and cytokines. See, for example, Schlessinger and Ullrich, Neuron 1992, 9, 383. The signals mediated by protein kinases have also been shown to control growth, death and differentiation in the cell by regulating the processes of the cell cycle.
Progression through the eukaryotic cell cycle is controlled by a family of protein kinases called cyclin dependent kinases (CDKs) and their interaction with a family of proteins termed cyclins (Myerson, et al., EMBO Journal 1992, 11, 2909-17). The coordinate activation and inactivation of different cyclin/CDK complexes is necessary for normal progression through the cell cycle (Pines, Trends in Biochemical Sciences 1993, 18, 195-7; Sherr, Cell 1993, 73, 1059-1065.). Both the critical G1-S and G2-M transitions are controlled by the activation of different cyclin/CDK activities. In G1, both cyclin D/CDK4 and cyclin E/CDK2 are thought to mediate the onset of S-phase. Progression through S-phase requires the activity of cyclin A/CDK2 whereas the activation of cyclin A/cdc2 (CDK1) and cyclin B/cdc2 are required for the onset of metaphase. It is not surprising, therefore, that the loss of control of CDK regulation is a frequent event in hyperproliferative diseases and cancer. (Pines, Current Opinion in Cell Biology 1992, 4, 144-8; Lees, Current Opinion in Cell Biology 1995, 7, 773-80; Hunter and Pines, Cell 1994, 79, 573-82).
Consequently, inhibition of CDKs may prevent progression in the cell cycle in normal cells and limit the toxicity of cytotoxics which act in S-phase, G2 or mitosis. Such disruption of the cell cycle of normal proliferating cells should therefore protect proliferating cells such as hair follicles and epithelial mucosa from the effects of cytotoxic agents and thereby provide a potent treatment for side effects associated with cancer chemo- and radiotherapies.
The present inventors have discovered novel fused pyridazine derivatives, which are inhibitors of CDK, specifically CDK2 and CDK4 activity. Such pyridazine derivatives are useful in the treatment of CIA and mucositis as well as cancer.